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NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)

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Interpretation:
Likely pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
6 (Most recent: Sep 27, 2021)
Last evaluated:
Jun 18, 2021
Accession:
VCV000252083.7
Variation ID:
252083
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu)

Allele ID
246378
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11120101 (GRCh38) GRCh38 UCSC
19: 11230777 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_000527.4:c.1855T>C NP_000518.1:p.Phe619Leu missense
NC_000019.10:g.11120101T>C
NC_000019.9:g.11230777T>C
... more HGVS
Protein change
F619L, F578L, F492L, F451L
Other names
NP_000518.1:p.F619L
NM_000527.5(LDLR):c.1855T>C
Canonical SPDI
NC_000019.10:11120100:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Links
ClinGen: CA037227
LDLR-LOVD, British Heart Foundation: LDLR_000570
dbSNP: rs747134711
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 5 reviewed by expert panel Jun 18, 2021 RCV000237217.8
Uncertain significance 1 criteria provided, single submitter Feb 11, 2020 RCV001182067.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
LDLR Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3091 3291

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Jun 18, 2021)
reviewed by expert panel
Method: curation
Familial hypercholesterolemia 1
(Semidominant inheritance)
Allele origin: germline
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001960933.1
Submitted: (Sep 27, 2021)
Evidence details
Publications
PubMed (1)
Other databases
https://erepo.clinicalgenome.org…
Comment:
NM_000527.5(LDLR):c.1855T>C (p.Phe619Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS3_Supporting, PS4_Supporting) as defined by the ClinGen … (more)
Likely pathogenic
(Mar 25, 2016)
criteria provided, single submitter
Method: literature only
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline
LDLR-LOVD, British Heart Foundation
Accession: SCV000295715.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Dec 16, 2016)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503426.1
Submitted: (Jan 23, 2017)
Evidence details
Comment:
subject mutated among 2600 FH index cases screened = 1 / Other mutation at same codon/Software predictions: Conflicting
Uncertain significance
(Aug 22, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
(Autosomal dominant inheritance)
Allele origin: germline
Robarts Research Institute,Western University
Accession: SCV000484688.2
Submitted: (Aug 22, 2019)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Feb 11, 2020)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001347390.1
Submitted: (May 19, 2020)
Comment:
This missense variant (also known as p.Phe598Leu in the mature protein) replaces phenylalanine with leucine at codon 619 of the LDLR protein. Computational prediction suggests … (more)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606541.1
Submitted: (Apr 25, 2017)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. Wang J Arteriosclerosis, thrombosis, and vascular biology 2016 PMID: 27765764
Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia. The Familial Hypercholesterolaemia Regression Study Group. Sun XM Arteriosclerosis, thrombosis, and vascular biology 1997 PMID: 9409298
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0295e6fb-e527-4826-a143-03161d46853d - - - -

Text-mined citations for rs747134711...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 21, 2021